This invention relates generally to novel 1,2-disubstituted cyclic matrix metalloproteases and TNF-xcex1 inhibitors and pharmaceutical compositions containing the same and methods of using the same.
There is now a body of evidence that metalloproteases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMPs (tissue inhibitors of metalloprotease), which form inactive complexes with the MP""s.
Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A, 1970, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteases. The available evidence supports that it is the metalloproteases that are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). In addition, aggrecanase has been identified as providing the specific cleavage product of proteoglycan found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22).
Therefore, metalloproteases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25, 175-184, AP, San Diego, 1990).
Tumor necrosis factor (TNF) is a cell-associated cytokine that is processed from a 26 kd precursor form to a 17 kd active form. TNF has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF with specific antibodies can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependent diabetes melitus. (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22) and Crohn""s disease (MacDonald T. et al. Clin. Exp. Immunol. 81, 1990, 301).
Compounds which inhibit the production of TNF are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that a matrix metalloprotease or family of metalloproteases, hereafter known as TNF-convertases (TNF-C), as well as other MP""s are capable of cleaving TNF from its inactive to active form (Gearing et al Nature, 1994, 370, 555). This invention describes molecules that inhibit this conversion and hence the secretion of active TNF-xcex1 from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, malaria, Crohn""s disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, OA, RA, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may also have a particular advantage in diseases where both mechanisms are involved.
EP 0,780,286 describes MMP inhibitors of formula A: 
wherein Y can be NHOH, R1 and R2 can combine to form a cycloalkyl or heterocycloalkyl group, R3 and R4 can be a variety of groups including H, and R5 can be substituted aryl. Such compounds are not considered to be part of the present invention.
WO 97/20824 depicts MMP inhibitors of formula B: 
wherein ring V contains six atoms, Z is O or S, and Ar is an aryl or heteroaryl group. Ar is preferably a monocyclic aryl group with an optional para substituent or an unsubstituted monocyclic heteroaryl group. Compounds of this sort are not considered to be part of the present invention.
EP 0,818,442 illustrates MMP inhibitors of formula C: 
wherein Ar is optionally substituted phenyl or naphthyl, Z can be absent and X and Y can be a variety of substituents. Compounds like this are not considered to be part of the present invention.
WO 98/39316 presents MMP inhibitors of formula D: 
wherein R6 and R7 can combine to form a heterocycle and R1 can be a substituted aryl group. These types of compounds are not considered to be part of the present invention.
WO 97/32846 describes MMP inhibitors of formula E: 
wherein R1 can be a sulfonyl aryl group. Compounds of this sort are not considered to be part of the present invention.
The compounds of the present invention act as inhibitors of MPs, in particular aggrecanase and TNF-xcex1. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibition of aggrecanase, TNF-C, and other metalloproteases by molecules of the present invention indicates they are anti-inflammatory and should prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of OA and RA.
Accordingly, one object of the present invention is to provide novel cyclic hydroxamic acids useful as metalloprotease inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating inflammatory disorders, comprising: administering to a host, in need of such treatment, a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, p1, R1a, R1b, R2, R2a, R2b, R3, Ua, Xa, ya, Z, and Za are defined below, are effective metalloprotease inhibitors.
[1] Thus, in an embodiment, the present invention provides a novel compound of formula I: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from xe2x80x94COR5, xe2x80x94CO2H, CH2CO2H, xe2x80x94CO2R6, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94N(OH)CHO, xe2x80x94N(OH)COR5, xe2x80x94SH, xe2x80x94CH2SH, xe2x80x94SONHRa, xe2x80x94SN2H2Ra, xe2x80x94PO(OH)2, and xe2x80x94PO(OH)NHRa;
ring B is a 3-10 membered carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-1 carbonyl groups, 0-3 double bonds, and from 0-2 ring heteroatoms selected from O, N, NR2, and S(O)p, provided that ring B contains other than a Sxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94O bond and provided that Nxe2x80x94R2 forms other than an Nxe2x80x94O, Nxe2x80x94N, or Nxe2x80x94S bond;
Z is absent or selected from a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)O, OC(O), C(O)NRa1, NRa1C(O), OC(O)O, OC(O)NRa1, NRa1C(O)O, NRa1C(O)NRa1, S(O)p, S(O)pNRa1, NRa1S(O)p, and NRa1SO2NRa1;
Xa is absent or selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
ya is absent or selected from O, NRa1, S(O)p, and C(O);
Za is selected from a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R1a is selected from H, C1-4 alkyl, phenyl, benzyl, CH2OR3, and CH2NRaRa1;
R1b is selected from H, C1-4 alkyl, phenyl, benzyl, CH2OR3, and CH2NRaRa1;
alternatively, R1a and R1b combine to form a 3-6 membered ring consisting of: carbon atoms and 0-1 heteroatoms selected from O, NRa, and S(O)p;
R2 is selected from Q, C1-10 alkylene-Q substituted with 0-3 Rb1, C2-10 alkenylene-Q substituted with 0-3 Rb1, C2-10 alkynylene-Q substituted with 0-3 Rb1, (CRaRa1)r1O(CRaRa1)rxe2x80x94Q, (CRaRa1l)r1NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O) (CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1OC(O) (CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)NRaRa1, (CRaRa1)r1C(O)NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRaC(O) (CRaRa1)rxe2x80x94Q, (CRaRa1)r1OC(O)O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1OC(O)NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRaC(O)O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRaC(O)NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1S(O)p(CRaRa1)rxe2x80x94Q, (CRaRa1)r1SO2NRa(CRaR a1)rxe2x80x94Q, (CRaRa1)r1NRaSO2(CRaRa1)rxe2x80x94Q, and (CRaRa1)r1NRaSO2NRa(CRaRa1)rxe2x80x94Q;
R2a is selected from H, C1-6 alkyl, ORa, NRaRa1, and S(O)pRa;
R2b is H or C1-6 alkyl;
Q is selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rd and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rd;
R3, at each occurrence, is selected from Q1, C1-6 alkylene-Q1, C2-6 alkenylene-Q1, C2-6 alkynylene-Q1, (CRaRa1)r1O(CH2)rxe2x80x94Q1, (CRaRa1)r1NRa(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1NRaC(O)(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1C(O)NRa(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1C(O) (CRaRa1)rxe2x80x94Q1, (CRaRa1)r1C(O)O(CRaRa1)rQ1, (CRaRa12)r1S(O)p(CRaRa1)rxe2x80x94Q1, and (CRaRa1)r1SO2NRa(CRaRa1)rxe2x80x94Q1;
alternatively, when two R3s are attached to the same carbon atom, they combine to form a 3-8 membered carbocyclic or heterocyclic ring consisting of: carbon atoms and 0-3 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rd;
Q1 is selected from H, phenyl substituted with 0-3 Rd, naphthyl substituted with 0-3 Rd and a 5-10 membered heteroaryl consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rd;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
alternatively, Ra and Ra1 when attached to a nitrogen are taken together with the nitrogen to which they are attached to form a 5 or 6 membered ring comprising carbon atoms and from 0-1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)O, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, and CF2CF3;
Rb1, at each occurrence, is independently selected from ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, and NRaRa1;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)O, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS (O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, CF2CF3, C3-10 carbocyclic residue and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)O, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, CF2CF3, C3-10 carbocyclic residue and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
R5, at each occurrence, is selected from C1-10 alkyl substituted with 0-2 Rb, and C1-8 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(Ra)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, and xe2x80x94CH(R8)OC(xe2x95x90O)OR9;
R7 is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7ais selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-8 alkyl substituted with 1-2 Rf, C3-8 cycloalkyl substituted with 1-2 Rf, and phenyl substituted with 0-2 Rb;
Rf, at each occurrence, is selected from C1-4 alkyl, C3-8 cycloalkyl, C1-5 alkoxy, and phenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
p1 is 0, 1, or 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
r1, at each occurrence, is selected from 0, 1, 2, 3, and 4.
[2] In a preferred embodiment, the present invention provides a novel compound of formula II: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94N(OH)CHO, xe2x80x94N(OH)COR5, xe2x80x94SH, and xe2x80x94CH2SH;
ring B is a 4-7 membered carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-1 carbonyl groups, 0-3 double bonds, and from 0-2 ring heteroatoms selected from O, N, and NR2, provided that ring B contains other than an Oxe2x80x94O, bond and provided that Nxe2x80x94R2 forms other than an Nxe2x80x94O, Nxe2x80x94N, or Nxe2x80x94S bond;
Z is absent or selected from a C3-6 carbocyclic residue substituted with 0-4 Rb and a 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)O, C(O)NRa1, NRa1C(O), S(O)p, and S(O)pNRa1;
Xa is absent or selected from C1-4 alkylene, C2-4 alkenylene, and C2-4 alkynylene;
Ya is absent or selected from O and NRa1;
Za is selected from H, a C3-10 carbocyclic residue substituted with 0-5 Rc and a 5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, (CRaRa1)r1O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O) (CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)O(CRaRa1)rxe2x80x94Q, (CRaRa1)rC(O)NRaRa1, (CRaRa1)r1C(O)NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1S(O)p(CRaRa1)rxe2x80x94Q, and (CRaRa1)r1SO2NRa(CRaRa1)rxe2x80x94Q;
Q is selected from H, a C3-6 carbocyclic residue substituted with 0-5 Rd, and a 5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rd;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
alternatively, Ra and Ra1 when attached to a nitrogen are taken together with the nitrogen to which they are attached to form a 5 or 6 membered ring comprising carbon atoms and from 0-1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, C3-6 carbocyclic residue and a 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, C3-6 carbocyclic residue and a 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
R5, at each occurrence, is selected from C1-6 alkyl substituted with 0-2 Rb, and C1-4 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(Ra)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, and xe2x80x94CH(R8)OC(xe2x95x90O)OR9;
R7 is selected from H and C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7a is selected from H and C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-6 alkyl substituted with 1-2 Rf, C3-6 cycloalkyl substituted with 1-2 Rf, and phenyl substituted with 0-2 Rb;
Rf, at each occurrence, is selected from CH1-4 alkyl; C3-6 cycloalkyl, C1-5 alkoxy, and phenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
r1, at each occurrence, is selected from 0, 1, 2, 3, and 4.
[3] In a more preferred embodiment, the present invention provides a novel compound of formula III: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94N(OH)CHO, and xe2x80x94N(OH)COR5;
B1 is selected from NR2, O, and CHR2, provided that Nxe2x80x94R2 forms other than an Nxe2x80x94O, Nxe2x80x94N, or Nxe2x80x94S bond;
Z is absent or selected from a C5-6 carbocyclic residue substituted with 0-3 Rb and a 5-6 membered heteroaryl comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)NRa1, S(O)p, and S(O)pNRa1;
Xa is absent or selected from C1-2 alkylene and C2-4 alkynylene;
Ya is absent or selected from O and NRa1;
Za is selected from H, a C5-6 carbocyclic residue substituted with 0-3 Rc and a 5-10 membered heteroaryl comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rc;
provided that z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, (CRaRa1)r1O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)O(CRaRa1)rxe2x80x94Q, (CRaRa2)r1C(O)NRaRa1, (CRaRa2)r1C(O)NRa(CRaRa1)rxe2x80x94Q, and (CRaRa1)r1S(O)p(CRaRa1)rxe2x80x94Q;
Q is selected from H, a C3-6 carbocyclic residue substituted with 0-3 Rd and a 5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rd;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, xe2x95x90O, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3 and phenyl;
R5, at each occurrence, is selected from C1-4 alkyl substituted with 0-2 Rb, and C1-4 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4;
r1, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
s and s1 combine to total 1, 2, 3, or 4.
[4] In an even more preferred embodiment, the present invention provides a novel compound of formula IV: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
Z is absent or selected from phenyl substituted with 0-3 Rb and pyridyl substituted with 0-3 Rb;
Ua is absent or is O;
Xa is absent or is selected from CH2, CH2CH2, and C2-4 alkynylene;
Ya is absent or is O;
Za is selected from H, phenyl substituted with 0-3 Rc, pyridyl substituted with 0-3 Rc, and quinolinyl substituted with 0-3 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, or Oxe2x80x94O group;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkynylene-Q, (CRaRa1)r1O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRa(CRaRa1)rxe2x80x94Q, C(O) (CRaRa1)rxe2x80x94Q, C(O)O(CRaRa1)rxe2x80x94Q, C(O)NRa(CRaRa1)rxe2x80x94Q, and S(O)p(CRaRa1)rxe2x80x94Q;
Q is selected from H, cyclopropyl substituted with 0-1 Rd, cyclobutyl substituted with 0-1 Rd, cyclopentyl substituted with 0-1 Rd, cyclohexyl substituted with 0-1 Rd, phenyl substituted with 0-2 Rd and a heteroaryl substituted with 0-3 Rd, wherein the heteroaryl is selected from pyridyl, quinolinyl, thiazolyl, furanyl, imidazolyl, and isoxazolyl;
Ra, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Ra1, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Ra2, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, xe2x95x90O, NRaRa1, C(O)Ra, C(Q)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3 and phenyl;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3;
r1, at each occurrence, is selected from 0, 1, 2, and 3; and,
s and s1 combine to total 2, 3, or 4.
[5] In another preferred embodiment, the present invention provides a novel compound selected from the group:
(3R,4S)-N-hydroxy-1-methyl-3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-4-piperidinecarboxamide;
(3R,4S)-N-hydroxy-1-isopropyl-3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-4-piperidinecarboxamide;
tert-butyl (3S,4S)-4-[(hydroxyamino)carbonyl]-3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-1-piperidinecarboxylate;
(3S, 4S)-N-hydroxy-3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-4-piperidinecarboxamide;
(3S,4S)-N-hydroxy-1-methyl-3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-4-piperidinecarboxamide;
(3S, 4S)-N-hydroxy-1-isopropyl-3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-4-piperidinecarboxamide;
(3S,4S)-N-hydroxy-3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-1-propyl-4-piperidinecarboxamide;
(3S, 4S)-1-butyl-N-hydroxy-3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-4-piperidinecarboxamide;
(3S,4S)-N-hydroxy-1-isobutyl-3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-4-piperidinecarboxamide;
(3S,4S)-N-hydroxy-3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-1-(2-propynyl)-4-piperidinecarboxamide;
(3S,4S)-1-allyl-N-hydroxy-3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-4-piperidinecarboxamide;
tert-butyl (3R,4R)-3-[(hydroxyamino)carbonyl]-4-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-1-piperidinecarboxylate;
(3R, 4R)-N-hydroxy-4-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-piperidinecarboxamide;
(3R,4R)-N-hydroxy-1-methyl-4-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-piperidinecarboxamide;
(3R,4R)-N-hydroxy-1-isopropyl-4-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-piperidinecarboxamide;
(2S,3S)-N-hydroxy-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-piperidinecarboxamide;
(2S,3S)-N-hydroxy-1-methyl-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-piperidinecarboxamide;
(2R, 3S)-N-hydroxy-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-piperidinecarboxamide;
(2R, 3S)-N-hydroxy-1-methyl-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-piperidinecarboxamide;
(2R,3S)-N-hydroxy-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-pyrrolidinecarboxamide;
(2R,3S)-N-hydroxy-1-methyl-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-pyrrolidinecarboxamide;
tert-butyl (3R,4S)-3-[(hydroxyamino)carbonyl]-4-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-1-pyrrolidinecarboxylate;
(3R,4S)-N-hydroxy-4-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-pyrrolidinecarboxamide;
(3R,4S)-N-hydroxy-1-isopropyl-4-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-pyrrolidinecarboxamide;
(3R,4S)-N-hydroxy-4-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-1-(2-propynyl)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-3-({[4-(3-methoxyphenoxy)phenyl]sulfonyl}methyl)-4-piperidinecarboxamide;
(3S,4S)-3-({[4-(3-chlorophenoxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide;
(3S, 4S)-N-hydroxy-3-({[4-(3-methylphenoxy)phenyl]sulfonyl}methyl)-4-piperidinecarboxamide;
(2R,3S)-N-hydroxy-1-isopropyl-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-pyrrolidinecarboxamide;
(2R, 3S)-N-hydroxy-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-1-(methylsulfonyl)-3-pyrrolidinecarboxamide;
(2R,3S)-1-(2-furoyl)-N-hydroxy-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-pyrrolidinecarboxamide;
(2R,3S)-1-(3-furoyl)-N-hydroxy-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-pyrrolidinecarboxamide;
(2R,3S)-N-hydroxy-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-1-(tetrahydro-2-furanylcarbonyl)-3-pyrrolidinecarboxamide;
(2R,3S)-N-hydroxy-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-1-(tetrahydro-3-furanylcarbonyl)-3-pyrrolidinecarboxamide; and,
(2R,3S)-1-acetyl-N-hydroxy-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-pyrrolidinecarboxamide;
or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating an inflammatory disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat an inflammatory disorder.
In another embodiment, the present invention provides a novel method of treating a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating, wherein the disease or condition is referred to as acute infection, acute phase response, age related macular degeneration, alcoholism, allergy, allergic asthma, aneurism, anorexia, aortic aneurism, asthma, athersclerosis, atopic dermatitis, autoimmune disease, autoimmune hepatitis, Bechet""s disease, cachexia, calcium pyrophosphate dihydrate deposition disease, cardiovascular effects, chronic fatigue syndrome, chronic obstruction pulmonary disease, coagulation, congestive heart failure, corneal ulceration, Crohn""s disease, enteropathic arthropathy, Felty""s syndrome, fever, fibromyalgia syndrome, fibrotic disease, gingivitis, glucocorticoid withdrawal syndrome, gout, graft versus host disease, hemorrhage, HIV infection, hyperoxic alveolar injury, infectious arthritis, inflammation, intermittent hydrarthrosis, Lyme disease, meningitis, multiple sclerosis, myasthenia gravis, mycobacterial infection, neovascular glaucoma, osteoarthritis, pelvic inflammatory disease, periodontitis, polymyositis/dermatomyositis, post-ischaemic reperfusion injury, post-radiation asthenia, psoriasis, psoriatic arthritis, pulmonary emphysema, pydoderma gangrenosum, relapsing polychondritis, Reiter""s syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sepsis syndrome, Still""s disease, shock, Sjogren""s syndrome, skin inflammatory diseases, solid tumor growth and tumor invasion by secondary metastases, spondylitis, stroke, systemic lupus erythematosus, ulcerative colitis, uveitis, vasculitis, and Wegener""s granulomatosis.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional more preferred embodiments. It is also to be understood that each individual element of the preferred embodiments is intended to be taken individually as its own independent preferred embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Geometric isomers of double bonds such as olefins and Cxe2x95x90N double bonds can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., Rb) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-10 alkyl (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbonxe2x80x94carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C2-10 alkenyl (or alkenylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbonxe2x80x94carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C2-10 alkynyl (or alkynylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic groupxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic groupxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, NH, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc . . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
As used herein, xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit a desired metalloprotease in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased anti-inflammatory effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and work up procedure, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
Compounds of formula I where A is a hydroxamic acid can be prepared using the methods described in Schemes 1-4. In Scheme 1, an alcohol 1 is converted to a halide or sulfonate 2. Displacement of 2 with a thiol using a base such as NaH produces the sulfide 3. Oxidation using an oxidant such as Oxone(copyright) gives rise to a sulfone derivative 4. Removal of the tert-butyl followed by coupling with 5 hydroxylamine using a coupling agent such as BOP affords the hydroxamic acid 5 (Scheme 1). 
Alternatively, compound 5 can be prepared from a lactone 6 (Scheme 2). Ring opening of lactone 6 with a thiol using a base such as sodium hydride gives rise to an acid 7. Oxidation using an oxidant such as Oxone(copyright) produces a sulfone derivative 8. Coupling of 8 with hydroxylamine using a coupling agent such as BOP affords the hydroxamic acid 5. 
Intermediate 2 can be reacted with 4-mercaptophenol using a base such as sodium hydride to give the sulfide intermediate 9. Compound 9 can also be prepared from the lactone 6 by ring opening with 4-mercaptophenol followed by esterification with XR11. Thioether 9 can be used as a common intermediate for derivatization at the phenol moiety. Alkylation of 9 with ArCH2X using a base provides the intermediate 10a. A copper (II) reaction of 9 with an aryl boronic acid gives rise to a biphenylether 10b. Treatment of 9 with triflic anhydride followed by a Suzuki reaction with an aryl boronic acid produces the biphenyl intermediate 10c. The intermediates 10a-10c where R11 is a tert-butyl group are then converted to hydroxamic acids following the procedures described in Scheme 1.
When R11 is a methyl group in intermediate 10, methyl ester 11 is subjected to an oxidation using an oxidant such as Oxone(copyright) to give a sulfone derivative 12. Treatment of 12 with a hydroxylamine solution in methanol provides the hydroxamic acid 13 (Scheme 4). 
When the B ring is a heterocycle such as a pyrrolidine or piperidine with a protecting group such as Boc on the nitrogen, the protecting group is removed using an acid such as TFA to give a secondary amine 15. Functionalization of the secondary amine by alkylation, reductive amination, acylation, or sulfonylation gives rise to a variety of analogs 16 such as tertiary amines, amides, carbamates, ureas, and sulfonamides. Ester 16 is converted to a hydroxamic acid using the procedures outlined in Scheme 1 and Scheme 4. 
The B ring in formula I can be constructed using the methods depicted in Schemes 6-10. The trans-3,4-disubstituted piperidine derivative 27 can be prepared following the sequence outlined in Scheme 6. Benzylation of N-Cbz-xcex2-amino acid 17 with benzyl bromide in a mixed solvent of DMF/THF using sodium hydride produces the N-benzylated product 18. The carboxylic acid 18 is then coupled with a chiral auxiliary (R)xe2x80x94XH (4-benzyl-2-oxazolidinone) using a coupling agent such as pivaloyl chloride. Alkylation of 19 with tert-butyl bromoacetate using LDA provides the tert-butyl ester 20 that is subjected to a hydrolysis using LiOH/H2O2. Alkylation of the carboxylic acid 21 with allyl bromide using LDA provides the allylated product 22 with a syn stereochemistry. The carboxylic acid 22 is converted to a benzyl ester 23 and the olefin is converted to an aldehyde 24 by ozonolysis. Hydrogenation using Pdxe2x80x94C as the catalyst gives rise to a piperidine derivative 25 that is subjected to a Boc protection. Borane reduction of 26 affords the alcohol 27. 
The cis-3,4-disubstituted piperidine derivatives can be prepared starting with 3,4-pyridine dicarboxylic acid 28 (Scheme 7). Hydrogenation using PtO2 as the catalyst in aqueous HCl followed by treatment with (Boc)2O using NaOH as base gives rise to N-Boc-cis-3,4-piperidine dicarboxylic acid 29. The acid is subjected to a treatment with acetic anhydride to give the anhydride 30. Sodium borohydride reduction produces two regioisomers of hydroxycarboxylic acid 31a and 31b. Cyclization by treatment with iodomethane provides two lactones 32a and 32b that are separated using flash chromatography. 
The trans-2,3-disubstituted piperidine derivative 40 can be prepared starting with L-aspartic acid xcex2-tert-butyl ester. Alkylation of 40 with benzyl bromide using potassium carbonate in DMF/DMSO provides the tribenzylated intermediate 34. An allyl group was introduced at the xcex2-position by subjecting 34 to a LiHMDS reaction with allyl bromide. After conversion of the olefin in 35 to an alcohol by treatment with 9-BBN, the two diastereomers were separated using flash chromatography. The syn diastereomer is then oxidized using an oxidant such as pyridinium dichromate to give the aldehyde 37. Hydrogenation gives rise to a piperidine derivative 38 that is subjected to a Boc protection. Borane reduction at the carboxylic acid provides the alcohol 40. 
The trans-2,3-disubstituted pyrrolidine derivative 46 can be prepared starting with N-Cbz-L-aspartic acid xcex1-benzyl xcex2-butyl esters 41 (Scheme 9). Alkylation of 41 with allyl bromide using LDA or LHMDS gives rise to the xcex2-allylated product as a mixture of two diastereomers that are seperated using flash chromatography. The syn diastereomer 42 is subjected to ozonolysis to give an aldehyde 43. Hydrogenation provides a pyrrolidine derivative 44. Following Boc protection, the carboxylic acid 45 was subjected to a borane reduction to afford the alcohol 46. 
The trans-3,4-disubstituted pyrrolidine derivative 50 can be prepared commencing with benzyl tert-butyl fumarate 47 (Scheme 10). The pyrrolidine derivative 48 can be obtained by refluxing a mixture of 47, paraformaldehyde and glycine in toluene. Boc protection at the secondary amine is followed by hydrogenation to remove the benzyl group. Borane reduction at the carboxylic acid affords the alcohol 50. 
The cis-3,4-disubstituted pyrrolidine derivative 57 can be prepared using the sequence outlined in Scheme 11. The N-benzylpyrrolidine derivative 53 can be obtained by refluxing a mixture of N-benzylglycine 51, dimethyl maleate 52, and paraformaldehyde in toluene. Hydrogenation of 53 to remove the benzyl group is carried out in the presence of Boc anhydride that blocks the secondary amine generated. Saponification provides the acid 55 that is subjected to a treatment with acetic anhydride. Sodium borohydride reduction of the anhydride 56 provides the lactone 57. 
Alternatively, compounds of formula I can be synthesized by introducing an arylthioether at the beginning of the sequence. For example, the intermediate 65 can be prepared starting with N-Cbz-D-aspartic acid xcex2-tert-butyl ester 58. Reduction of 58 using borane provides an alcohol 59. The alcohol is converted to a mesylate 60 that is displaced with 4-mercaptophenol using a base such as sodium hydride to give the sulfide 61. Benzylation at the phenolic OH using potassium carbonate provides 62. Alkylation of 62 with allyl bromide using LDA is followed by Oxone(copyright) oxidation. The sulfone 63 is subjected to a 9-BBN reaction to give an alcohol that is oxidized using an oxidant such as pyridinium dichromate. Hydrogenation gives rise to a cis-2,3-disubstituted piperidine derivative the secondary amine of which is then blocked with a Boc group. The intermediate 65 can be converted to a variety of hydroxamic acids using the procedures described previously. 
The intermediate 63 can also be subjected to an ozonolysis to give aldehyde 66. Hydrogenation of 66 using a catalyst such as Pd-C gives rise to a cis-2,3-disubstituted pyrrolidine derivative 67. Boc protection at the amino affords the intermediate 68 which can be transformed to a variety of hydroxamic acid following the procedures described previously. 
One diastereomer of a compound of Formula I may display superior activity compared with the others. Thus, the following stereochemistries are considered to be a part of the present invention. 
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al, Tetr. Lett. 1995, 36, 8937-8940.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.